Pharmaceutical compositions containing doravirine, tenofovir disoproxil fumarate and lamivudine

ABSTRACT

The instant invention relates to pharmaceutical compositions comprising doravirine, tenofovir disoproxil fumarate and lamivudine. These compositions are useful for the treatment of HIV infection. Also disclosed are processes for making said pharmaceutical compositions.

BACKGROUND OF THE INVENTION

This invention relates to pharmaceutical compositions comprisingdoravirine, tenofovir disoproxil fumarate and lamivudine. Thesecompositions are useful for the treatment of human immunodeficiencyvirus (HIV) infection.

Specifically, this invention relates to single tablet fixed-dosecombinations of doravirine, lamivudine and tenofovir disoproxilfumarate. A fixed-dose combination is desired and useful for thetreatment of HIV infection from both compliance and conveniencestandpoints.

The novel pharmaceutical compositions of the instant invention addressthe need for incorporation of high doses of doravirine, lamivudine andtenofovir disoproxil fumarate into a compact, single-unit dosage formwhile still maintaining comparable bioperformance to those of co-doseddoravirine, lamivudine and tenofovir disoproxil fumarate single entityformulations.

SUMMARY OF THE INVENTION

The instant invention relates to pharmaceutical compositions comprisingdoravirine, tenofovir disoproxil fumarate and lamivudine. Thesecompositions are useful for the treatment of HIV infection. Alsodisclosed are processes for making said pharmaceutical compositions.

DETAILED DESCRIPTION OF THE INVENTION

The pharmaceutical compositions of the present invention are useful inthe treatment of HIV infection. The novel pharmaceutical compositions ofthe instant invention address the need for incorporation of high dosesof doravirine, lamivudine and tenofovir disoproxil fumarate into acompact, single-unit dosage form while still maintaining comparablebioperformance to co-dosed single entities of doravirine, lamivudine andtenofovir disoproxil fumarate.

An embodiment of the instant invention comprises a bilayer tablet thatincorporates high loading of an amorphous dispersion formulation ofdoravirine in one layer and high loadings of crystalline formulations oflamivudine and tenofovir disoproxil fumarate in a separate layer. Theresulting bilayer tablets are compact, single-unit dosage forms thathave bioperformance comparable to those of individually co-doseddoravirine, lamivudine and tenofovir disoproxil fumarate.

Doravirine is an HIV reverse transcriptase (RT) inhibitor having thechemical name3-chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrileand the following chemical structure:

Production and the ability of doravirine to inhibit HIV reversetranscriptase is illustrated in WO 2011/120133 A1, published on Oct. 6,2011, and U.S. Pat. No. 8,486,975, granted Jul. 16, 2013, both of whichare hereby incorporated by reference in their entirety.

Tenofovir disoproxil fumarate (which can be abbreviated as “TDF”) is anantiretroviral medication used to prevent and treat HIV/AIDS. It is ofthe nucleoside analog reverse transcriptase inhibitor (NRTI) class andis marketed under the tradename VIREAD®. TDF is disclosed in U.S. Pat.No. 5,922,695.

Lamivudine (2′,3′-dideoxy-3′-thiacytidine, commonly called 3TC) is anantiretroviral medication used to prevent and treat HIV/AIDS. It is ofthe nucleoside analog reverse transcriptase inhibitor (NRTI) class andis marketed under the tradename EPIVIR®. Lamivudine is also abbreviatedas “LAM.” Lamivudine and method of treating HIV using lamivudine aredisclosed in U.S. Pat. No. 5,047,407.

Doravirine is known to exist in three crystalline anhydrous forms,designated as Form I, Form II and Form III, and in an amorphous form. Anamorphous dispersion formulation of doravirine can be made byspray-drying doravirine with a polymer, such as hydroxypropyl methylcellulose acetate succinate (HPMCAS, also known as “hypromellose acetatesuccinate”), hydroxypropyl methyl cellulose phthalate, cellulose acetatephthalate, cellulose acetate trimellitate, methyl cellulose acetatephthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetateterephthalate, cellulose acetate isophthalate, polyvinylpyrrolidinone orpolyvinylpyrrolidinone-polyvinylacetate copolymers. In a class of theinvention, the amorphous dispersion formulation of doravirine is made byspray-drying doravirine with hydroxypropyl methyl cellulose acetatesuccinate (HPMCAS-L), which significantly improves the bioavailabilityof doravirine.

However, the resulting amorphous dispersion formulation of doravirineposes many unique challenges, including physical stability, sincedoravirine is a strong crystallizer. Doravirine was found to crystallizereadily in the absence of a polymer and to have a high melting point of286° C. (see, PCT International Publication WO 2015/077273, which ishereby incorporated by reference in its entirety). Neat amorphousdoravirine generated by spray-drying crystallizes within 2 weeks whenstored in an open container at 5° C./ambient relative humidity (RH), 30°C./65% RH, 40° C./75% RH, and 60° C./ambient RH. For spray-drieddispersions of doravirine and HPMCAS, crystallization was observed at35% drug loading after 16 weeks of storage and at 40% drug loading after8 weeks of storage at 40° C./75% RH (open). Other factors can affectphysical stability, including inherent tendency of the drug tocrystallize, drug loading in the dispersion, type of polymers used,hygroscopicity of the formulation and other factors.

In addition to challenges associated with physical stability,dissolution of the amorphous dispersion of doravirine is a concern dueto a kinetic supersaturation effect. The composition comprising theamorphous dispersion of doravirine (doravirine and a polymer) provides ahigher maximum aqueous concentration of doravirine relative to a controlcomposition having the same concentration of doravirine but without thepolymer. This supersaturation effect is transient and relies on rapiddissolution of the drug from the tablet.

Furthermore, there are processing issues due to atypical compactionproperties associated with the amorphous dispersion of doravirine. Thecompactability of doravirine spray dried dispersion is directlycorrelated to the bulk density of the dispersion. Higher bulk densityleads to lower tensile strength tablets. Also, recompactability of thespray dried dispersion formulations, post roller compaction is also aconcern. A relatively high roller compaction force results in lowerfinal compactability. In certain cases, tablets of formulationscontaining doravirine spray dried dispersions with high bulk densityshow failure upon compression, due to low tensile strength (see, PCTInternational Publication WO2015/077273).

What is needed is a formulation that can consistently deliver high dosesof doravirine without encountering the observed issues related tophysical stability, kinetic supersaturation effect and processing.

The pharmaceutical compositions of the present invention, which arebilayer tablets, comprise an amorphous dispersion formulation ofdoravirine in the first layer, and lamivudine and tenofovir disoproxilfumarate in the second layer.

In an embodiment of the invention, the first layer comprises anamorphous dispersion formulation of doravirine, a glidant, a diluent, adisintegrant and lubricants. In a class of the invention, the firstlayer comprises from about 25% to 75% by weight of an amorphousdispersion formulation of doravirine, and from about 25% to 75% byweight of excipients comprising glidant, diluents, disintegrants andlubricants. In a subclass of the invention, the first layer comprisesfrom about 50% to 65% by weight of an amorphous dispersion formulationof doravirine, about 24% to 46% by weight of diluents, and about 0.1% to1% by weight of glidants, about 4% to 8% by weight of disintegrants,about 0.25% to 2% by weight of lubricants.

In an embodiment of the invention, the second layer compriseslamivudine, tenofovir disoproxil fumarate, a glidant, a diluent, adisintegrant, and lubricants. In a class of the invention, the secondlayer comprises from about 15% to 45% by weight of lamivudine, fromabout 15% to 45% by weight of tenofovir disoproxil fumarate, and fromabout 10% to 70% by weight of excipients comprising glidant, diluents,disintegrants and lubricants. In a subclass of the invention, the firstlayer comprises from about 30% to 40% by weight of lamivudine, fromabout 30% to 40% by weight of tenofovir disoproxil fumarate, about 0.1%to 2% by weight of glidants, about 6% to 38% by weight of diluents,about 2% to 8% by weight of disintegrants, about 0.25% to 4% by weightof lubricants.

Optionally, the pharmaceutical compositions are film coated. Thepharmaceutical compositions of the instant invention may also comprise apolishing aid such as carnauba wax, that among other uses, aids handlingof the final product.

The pharmaceutical compositions of the present invention may contain oneor more additional formulation ingredients that may be selected from awide variety of excipients known in the pharmaceutical formulation art.According to the desired properties of the compositions, any number ofingredients may be selected, alone or in combination, based upon theirknown uses in preparing tablet compositions. Such ingredients include,but are not limited to, diluents, binders, compression aids,disintegrants, lubricants, glidants, stabilizers (such as dessicatingamorphous silica), flavors, flavor enhancers, sweeteners, preservatives,colorants and coatings.

In an embodiment of the invention, the glidant, or flow aid, iscolloidal silica, silicone dioxide, talc or starch. In a class of theinvention, the glidant is colloidal silica.

In an embodiment of the invention, the diluents are selected from thegroup consisting of lactose, lactose anhydrous, lactose monohydrate,mannitol, microcrystalline cellulose, calcium phosphate, calciumphosphate dibasic, calcium carbonate and magnesium carbonate. In a classof the embodiment, the diluents are lactose monohydrate andmicrocrystalline cellulose.

In an embodiment of the invention the disintegrant is croscarmellosesodium, starch, crospovidone, sodium starch glycolate or any mixturesthereof. In a class of the embodiment, the disintegrant iscroscarmellose sodium.

In an embodiment of the invention, the lubricant is magnesium stearate,stearic acid or sodium stearyl fumarate. In a class of the embodiment,the lubricants used are magnesium stearate and sodium stearyl fumarate,stearic acid or mixtures thereof.

In an embodiment of the invention, the pharmaceutical composition has afilm coat. In a class of the invention, the film coating is an aqueousfilm coating. In a subclass of the invention, the film coating compriseshydroxypropylmethylcellulose, such as Opadry® II. Opadry® II, which isavailable from Colorcon, Inc., Harleysville, Pa., contains hydroxypropylmethyl cellulose (also known as “HPMC” or “hypromellose”), titaniumdioxide, lactose monohydrate, triacetin and iron oxide yellow.

In an embodiment of the invention, the pharmaceutical composition has apolishing aid. In a class of the invention, the polishing aid iscarnauba wax.

In an embodiment of the invention, the first layer comprises a glidantthat is colloidal silica; a diluent that is microcrystalline cellulose;a disintegrant that is croscarmellose sodium; and a lubricant that ismagnesium stearate.

In an embodiment of the invention, the second layer comprises a glidantthat is colloidal silica; a diluent that is microcrystalline cellulose;a disintegrant that is croscarmellose sodium; and lubricants that aremagnesium stearate and sodium stearyl fumarate.

The term “tablet” as used herein is intended to encompass compressedpharmaceutical dosage formulations of all shapes and sizes, whetheruncoated or coated. Substances which may be used for coating includehydroxypropylmethylcellulose, hydroxypropylcellulose, titanium dioxide,talc, sweeteners and colorants.

The novel pharmaceutical compositions of the instant invention addressthe need for incorporation of high doses of doravirine, lamivudine andtenofovir disoproxil fumarate into a compact, single-unit dosage formwhile still maintaining comparable bioperformance to formulations ofindividually co-dosed doravirine, lamivudine and tenofovir disoproxilfumarate.

Initial efforts to simply combine the three active ingredients into ahomogeneous composition were unsuccessful. At first, the amorphousdispersion formulation of doravirine, lamivudine and tenofovirdisoproxil fumarate were roller-compacted as a single granulation andcompressed into a monolithic tablet of <1.6 grams. However, the tabletdisintegration time was very long (more than 30 min), and the in-vitrodissolution was poor. Subsequent attempts were made to prepare separategranulations for the amorphous dispersion of doravirine and forlamivudine and tenofovir disoproxil fumarate and compress the combinedgranulations into a monolithic tablet of <1.6 grams. These attempts alsoresulted in relatively slow tablet disintegration and slow dissolutionof doravirine.

In an effort to improve the in vitro and in vivo performance of thedoravirine formulation, a bilayer configuration wherein the dissolutionof the doravirine moiety is not impeded by the tenofovir/lamivudineformulations was developed. Historically, a bilayer tablet configurationhas been utilized to formulate active agents with physical or chemicalincompatabilities resulting in degradation of interactions such as thosewhich slow down dissolution and lower bioperformance. Doravirine is alow solubility compound classified as a class II compound based on thebiopharmaceutics classification system. Hence, it is critical that therelease of the active from the fixed dose combination mimics the releasefrom the single entity formulation to ensure comparable efficacy. Forthe soluble actives, tenofovir disoproxil fumarate and lamivudine,co-granulating the two actives results in an eroding layer which ismechanistically different from the single entities which release thedrug through layer disintegration. Separating the lamivudine andtenofovir by incorporating lamivudine in the doravirine (first) layerspeeds up release of both lamivudine and tenofovir disoproxil fumarate,but considerably slows down doravirine release. Hence, achievingcomparable exposure from the fixed dose combination for these actives ischallenging, and the configuration in which these three moieties arepresented to ensure similar performance to single entities waspreviously unknown

The tablets of the instant invention incorporate high loading of anamorphous dispersion formulation of doravirine in one layer and highloadings of crystalline formulations of lamivudine and tenofovirdisoproxil fumarate in a separate layer. It was not until the discoveryof the instant invention that a physically and chemically stable tabletcould be obtained that contained all three active ingredients.

Increased complexity is imparted due to the hygroscopicity of theamorphous dispersion of doravirine in one layer owing to the polymer(for example, HPMCAS), and the susceptibility to hydrolytic degradationof the crystalline tenofovir disoproxil fumarate in the other layer. Thenovel pharmaceutical compositions of the instant invention address theneed for adequate physical and chemical stability of the tablets.Stability of the tablet, namely, chemical stability of tenofovirdisoproxil fumarate and physical stability of doravirine, was ensured bycontrolling water ingression into and water activity in the packagingconfiguration. One such way is through the use of desiccants in closedcontainers. Another approach to ensure chemical stability of tenofoviris through physical separation between tenofovir disoproxil fumarate andlamivudine, either within the layer or the dosage form. The separationof tenofovir and lamivudine can be done either as separate layers or asseparate granulations in the second layer.

In addition, the novel pharmaceutical compositions of the instantinvention address the need for process robustness upon scale up. Thefirst layer containing doravirine is susceptible to capping andinterfacial crack issues during bilayer compression as well as decappingand assay loss during processing. While interfacial cracking of bilayertablets due to low interfacial strength or differential swelling at hightemperature and relative humidity is well known, bilayer cracking due todeaeration issues of the amorphous dispersion in the first layer was notknown. The low bulk density of the amorphous dispersion formulation,designed to address loss on recompaction and ensure acceptableinterfacial strength between the two layers, is a key factor. Deaerationbased cracking was also not seen for the single entity formulation andis exacerbated for the large bilayer image. In some cases, these cracksmay not be initially present on the exterior of the tablet and hence maynot be visible to the naked eye but under conditions of stress such asheat and shear in a coating pan, the cracks can propagate towards theexterior and present themselves to the naked eye. A complex interplay ofroller compaction pressure, tamp force and tamp positioning optimizationduring bilayer compression was critical to resolving the bilayercracking. The second layer of lamivudine and tenofovir disoproxilfumarate is prone to roll sticking during roller compaction due to thehigh drug loadings and the inherent sticking propensity of tenofovir.The second layer formulation is also prone to extrusion during rollercompaction due to the low glass transition temperature of tenofovir.Mitigation of roll sticking and extrusion required optimal selection oflubricant systems and control of process temperature. The second layerformulation is also susceptible to layer edge chipping during filmcoating, due to the low tensile strength of the second layer. Edgechipping was circumvented through appropriate selection of film coatingsystems and optimization of coating process parameters.

Co-granulating tenofovir disoproxil fumarate and lamivudine results inan eroding layer which is mechanistically different from theformulations of the single entities, which release each drug throughlayer disintegration. It was not known if the mechanistically differentdissolution behaviors would have an impact on bioperformance.Furthermore, in the combined tablet, it was unknown whether there wouldbe an interaction between lamivudine and tenofovir disoproxil fumarate,which could result in chemical instability of tenofovir disoproxilfumarate.

The instant invention also addresses the chemical instability oftenofovir disoproxil fumarate, which hydrolyses to form a metabolite,tenofovir mono-POC (also known as “tenofovir monoisoproxil”). Thetenofovir disoproxil fumarate stability issue is exacerbated underhigher temperature and humidity conditions. These higher temperature andhumidity conditions can be found in Zone III (hot, dry climate, 30°C./35% RH)/Zone IV (hot, humid climate, 30° C./75% RH) countries, whichinclude countries in South America (Brazil), sub-Saharan Africa, SouthAsia (India), and Southeast Asia. Some of these geographical regionscoincidentally also happen to be areas where the HIV disease is mostprevalent thereby making it imperative for the product to be stable inthese hot and humid regions.

The pharmaceutical compositions of the instant invention are stable attemperatures up to 25° C. and up to 60% relative humidity for at least36 months. The pharmaceutical compositions of the instant invention arestable at temperatures up to 30° C. and up to 65% relative humidity forat least 24 months. Optionally, the packaging storage can include theuse of desiccants to further enhance the stability at high relativehumidity.

The instant invention also addresses the need for fixed dosepharmaceutical compositions containing doravirine, lamivudine andtenofovir disoproxil fumarate. A compact single-unit dosage form with animage size no larger than 1.6 grams was developed, comprising 100 mg ofdoravirine (equivalent to 500 mg of doravirine spray driedintermediate), 300 mg of lamivudine and 300 mg of tenofovir disoproxilfumarate. Also, a compact dosage form for two-unit administration(taking two tablets at a time) with an image size no larger than 1.0grams was developed, comprising 50 mg of doravirine (equivalent to 250mg of doravirine spray dried intermediate), 150 mg of lamivudine and 150mg of tenofovir disoproxil fumarate.

In another embodiment, the second layer can also contain lamivudine andtenofovir disoproxil fumarate which were separately granulated. As canbe seen in Example 7, lamivudine and tenofovir disoproxil fumarate weregranulated separately by roller compaction. In Example 8, lamivudine andtenofovir disoproxil fumarate were granulated separately by wetgranulation. Probe stability data indicated that the separategranulation approaches can improve the stability profile by reducing therate of tenofovir mono-POC (also called “mono-POC”) formation, as shownin Example 9 (accelerated study at 60° C./ambient, 3 weeks).

The following examples are given for the purpose of illustrating thepresent invention and shall not be construed as being limitations on thescope of the invention.

Example 1 50 mg Doravirine/150 mg Lamivudine/150 mg Tenofovir DisoproxilFumarate Bilayer Tablets

Amount Percentage in Components Function [mg] Each Layer Layer 1 Intra-granular Doravirine¹ Active 50.00 10.0% Hypromellose acetate succinate -Polymer 200.0 40.0% LG (HPMC-ASLG)¹ Acetone² Solvent — Water, Purified²Solvent — Microcrystalline Cellulose Diluent 107.5 21.5% LactoseMonohydrate Diluent 107.5 21.5% Croscarmellose Sodium Disintegrant 15.003.0% Colloidal Silica Glidant 2.50 0.50% Magnesium Stearate Lubricant1.25 0.25% Extra- granular Croscarmellose Sodium Disintegrant 15.00 3.0%Magnesium Stearate Lubricant 1.25 0.25% Layer 1 Weight 500.0 100.0%Layer 2 Intra- granular Lamivudine Active 150.0 30.0% TenofovirDisoproxil Fumarate Active 150.0 30.0% Microcrystalline CelluloseDiluent 120.0 24.0% Lactose Monohydrate Diluent 55.0 11.0%Croscarmellose Sodium Disintegrant 10.00 2.0% Magnesium StearateLubricant 1.25 0.25% Extra- granular Croscarmellose Sodium Disintegrant10.00 2.0% Magnesium Stearate Lubricant 3.75 0.75% Layer 2 Weight 500.0100.0% Core Tablet Weight 1000.0 Opadry II 39K Film Coat Film Coat 25.00Water, Purified² Solvent — Film-Coated Tablet Weight 1025.0 ¹Prepared asspray dried intermediate ²Removed during processing

Doravirine Layer Granulation.

Doravirine spray dried intermediate (see, PCT International PublicationWO2015/077273), microcrystalline cellulose, lactose monohydrate,colloidal silica (sieved thru 30 Mesh with microcrystalline cellulose)and croscarmellose sodium were blended in V-blender at 25 rpm for 10min. Magnesium stearate was sieved through 60 Mesh and added to theblender, which was blended at 25 rpm for additional 5 min. Thelubricated blend was roller-compacted using the Alexanderwerk WP-120 atthe following settings: 40 mm knurled roll, 37 bars, 2.0 mm gap, 1.6mm/0.8 mm CONIDUR screens. Then, croscarmellose sodium was added toV-blender and blended at 25 rpm for 5 min. Finally, magnesium stearatewas sieved through 60 Mesh and added to the blender, which was blendedat 25 rpm for additional 5 min.

LAM/TDF Blending and Roller Compaction.

TDF, lamivudine, microcrystalline cellulose, lactose monohydrate,croscarmellose sodium were sieved through 30 Mesh and blended inV-blender at 25 rpm for 10 min. Magnesium stearate was sieved through 60Mesh and added to the blender, which was blended at 25 rpm foradditional 5 min. The lubricated blend was roller-compacted using theAlexanderwerk WP-120 at the following settings: 40 mm knurled roll, 55bars, 2.0 mm gap, 1.6 mm/0.8 mm CONIDUR screens. Then, croscarmellosesodium was added to V-blender and blended at 25 rpm for 5 min. Finally,magnesium stearate was sieved through 60 Mesh and added to the blender,which was blended at 25 rpm for additional 5 min.

Bilayer Compression.

Doravirine lubricated granules (layer 1) and LAM/TDF lubricated granules(layer 2) were compressed into bilayer tablets on the Piccola pressusing the following parameters (oval tooling, 0.708″×0.354″, 500 mglayer 1 fill weight, 500 mg layer 2 fill weight, 20 kp hardness, 7.3 mmthickness, 1.7 kN tamping force, 18 kN main compression force, 10 rpmturret speed).

Film Coating.

An aqueous suspension of Opadry 39K, 15% by weight, was prepared. Thecompressed tablets were film-coated in the O'Hara (19″ pan) using thefollowing parameters (2.5 kg tablet load, exhaust temp=45° C., airflow=400 ft³/min, pan speed=10 rpm, spray rate=10 g/min).

Example 2 100 mg Doravirine/300 mg Lamivudine/300 mg TenofovirDisoproxil Fumarate Bilayer Tablets

Amount Percentage in Components Function [mg] Each Layer Layer 1 Intra-granular Doravirine¹ Active 100.0 12.8% Hypromellose acetate succinate -Polymer 400.0 51.3% LG (HPMC-ASLG)¹ Acetone² Solvent — Water, Purified²Solvent — Microcrystalline Cellulose Diluent 224.0 28.7% CroscarmelloseSodium Disintegrant 24.0  3.1% Colloidal Silica Glidant 4.00 0.51%Magnesium Stearate Lubricant 2.00 0.26% Extra- granular CroscarmelloseSodium Disintegrant 24.00  3.1% Magnesium Stearate Lubricant 2.00 0.26%Layer 1 Weight 780.0  100% Layer 2 Intra- granular Lamivudine Active300.0 38.5% Tenofovir Disoproxil Fumarate Active 300.0 38.5%Microcrystalline Cellulose Diluent 103.8 13.3% Croscarmellose SodiumDisintegrant 23.4  3.0% Colloidal Silica Glidant 7.80  1.0% MagnesiumStearate Lubricant 7.80  1.0% Sodium Stearyl Fumarate Lubricant 7.80 1.0% Extra- granular Croscarmellose Sodium Disintegrant 23.40  3.0%Magnesium Stearate Lubricant 6.00 0.77% Layer 2 Weight 780.0  100% CoreTablet Weight 1560 Opadry II 39K Film Coat Film Coat 39.00 Water,Purified² Solvent — Carnauba Wax Polishing 0.05 Aid Film-Coated TabletWeight 1599 ¹Prepared as spray dried intermediate ²Removed duringprocessing

Doravirine Layer Granulation.

Doravirine spray dried intermediate, microcrystalline cellulose,colloidal silica (sieved thru 30 Mesh with microcrystalline cellulose)and croscarmellose sodium were blended in 1800-L Bohle bin at 6 rpm for30 min. Magnesium stearate was sieved through 60 Mesh and added to theblender, which was blended at 6 rpm for 10 min. The lubricated blend wasroller-compacted using the Alexanderwerk WP-200 at the followingsettings: 75 mm knurled roll, 5.6 kN/cm, 2.0 mm gap, 2.0 mm/1.0 mmCONIDUR screens. Then, croscarmellose sodium was added to the Bohle binand blended at 6 rpm for 30 min. Finally, magnesium stearate was sievedthrough 60 Mesh and added to the blender, which was blended at 6 rpm foradditional 10 min.

LAM/TDF Blending and Roller Compaction.

TDF, lamivudine, microcrystalline cellulose, colloidal silica (sievedthru 30 mesh with microcrystalline cellulose), and croscarmellose sodiumwere blended in 1800-L Bohle bin at 6 rpm for 30 min. Sodium stearylfumarate and magnesium stearate was sieved through 60 Mesh and added tothe blender, which was blended at 6 rpm for 10 min. The lubricated blendwas roller-compacted using the Alexanderwerk WP-200 at the followingsettings: 75 mm knurled roll, 7.1 kN/cm, 2.0 mm gap, 2.0 mm/1.0 mm wirescreens. Then, croscarmellose sodium was added to the Bohle bin andblended at 6 rpm for 30 min. Finally, magnesium stearate was sievedthrough 60 Mesh and added to the blender, which was blended at 6 rpm for10 min.

Bilayer Compression.

Doravirine lubricated granules (layer 1) and LAM/TDF lubricated granules(layer 2) were compressed into bilayer tablets on the Fette 3090 press(49 stations) using the following parameters (oval tooling,0.850″×0.445″, 780 mg layer 1 fill weight, 780 mg layer 2 fill weight,23 kp hardness, 7.3 mm thickness, 5 kN tamping force, 37 kN maincompression force, 10 rpm turret speed).

Film Coating.

An aqueous suspension of Opadry 39K, yellow, 18% by weight, wasprepared. The compressed tablets were film-coated in the Vector FC 150L,using the following parameters (88 kg tablet load, exhaust temp=45° C.,air flow=1250 m³/hr, pan speed=4-5 rpm, spray rate=175-200 g/min).Carnauba wax was added to the film-coated tablets at the end.

Example 3 100 mg Doravirine/300 mg Lamivudine/300 mg TenofovirDisoproxil Fumarate Monolithic Tablets

Components Function Amount [mg] Granulation 1 (695 mg) Doravirine¹Active 100.0 Hypromellose acetate succinate - Polymer 400.0 LG(HPMC-ASLG)¹ Acetone² Solvent — Water, Purified² Solvent —Microcrystalline Cellulose Diluent 100.0 Lactose Monohydrate Diluent50.00 Croscarmellose Sodium Disintegrant 40.00 Colloidal Silica Glidant3.00 Magnesium Stearate Lubricant 2.00 Granulation 2 (700 mg) LamivudineActive 300.0 Tenofovir Disoproxil Fumarate Active 300.0 MicrocrystallineCellulose Diluent 50.00 Lactose Monohydrate Diluent 25.00 CroscarmelloseSodium Disintegrant 20.00 Magnesium Stearate Lubricant 5.00Extragranular (165 mg) Microcrystalline Cellulose Diluent 100.0Croscarmellose Sodium Disintegrant 60.00 Magnesium Stearate Lubricant5.00 Core Tablet Weight 1560 Opadry II 39K Film Coat Film Coat 39.00Water, Purified² Solvent — Film-Coated Tablet Weight 1599 ¹Prepared asspray dried intermediate ²Removed during processing

Doravirine Blending and Roller Compaction.

Doravirine spray dried intermediate, microcrystalline cellulose, lactosemonohydrate, colloidal silica and croscarmellose sodium were sievedthrough 30 Mesh and blended in V-blender at 25 rpm for 15 min. Magnesiumstearate was sieved through 60 Mesh and added to the blender, which wasblended at 25 rpm for additional 5 min. The lubricated blend wasroller-compacted using the Alexanderwerk WP-120 at the followingsettings: 40 mm knurled roll, 28 bars, 2.0 mm gap, 1.6 mm/0.8 mm CONIDURscreens.

LAM/TDF Blending and Roller Compaction.

TDF, lamivudine, microcrystalline cellulose, lactose monohydrate, andcroscarmellose sodium were sieved through 30 Mesh and blended inV-blender at 25 rpm for 15 min. Magnesium stearate was sieved through 60Mesh and added to the blender, which was blended at 25 rpm foradditional 5 min. The lubricated blend was roller-compacted using theAlexanderwerk WP-120 at the following settings: 40 mm knurled roll, 20bars, 2.0 mm gap, 1.6 mm/0.8 mm CONIDUR screens.

Granulation Blending and Lubrication.

Doravirine roller-compacted granules, LAM/TDF roller-compacted granules,microcrystalline cellulose (thru 30 Mesh), and croscarmellose sodium(thru 30 Mesh) were added to V-blender and blended at 25 rpm for 5 min.Then, magnesium stearate was sieved through 60 Mesh and added to theblender, which was blended at 25 rpm for additional 5 min.

Compression.

The lubricated blends were compressed on the Piccola press using thefollowing parameters (oval tooling, 0.745″×0.383″, 1560 mg fill weight,20 kp hardness, 9.7 mm thickness, 15 kN main compression force, 8 rpmturret speed).

Film Coating.

An aqueous suspension of Opadry 39K, 15% by weight, was prepared. Thecompressed tablets were film-coated in the O'Hara (19″ pan) using thefollowing parameters (2.82 kg tablet load, exhaust temp=45° C., airflow=250 ft³/min, pan speed=8 rpm, spray rate=30 g/min).

Example 4 Biocomparabiliy of Bilayer Tablets (50 mg/150 mg/150 mg),Monolithic Tablets (100 mg/300 mg/300 mg) and Co-Dosings

A biocomparability study was conducted to evaluate the relativebioavailability of the triple combinations of doravirine, lamivudine,and tenofovir disoproxil fumarate (two 50-mg bilayer tablets and a100-mg monolithic tablet) compared to the bioavailability of doravirine,lamivudine, and tenofovir disoproxil fumarate co-administered asindividual tablets (reference). The 50-mg bilayer formulation contained50 mg doravirine, 150 mg lamivudine, and 150 mg tenofovir disoproxilfumarate, while the 100-mg monolithic formulation contained 100 mgdoravirine, 300 mg lamivudine, and 300 mg tenofovir disoproxil fumarate.The data are summarized in the table below.

Doravirine PK 2 × 50/150/150 Bilayer³ 1 × 100/300/300 Monolithic^(b)Parameter GMR^(c) 90% CI GMR 90% CI AUC0-∞ 1.00 0.931-1.08 0.8580.800-0.919 Cmax 0.977 0.893-1.07 0.713 0.652-0.781 C24 hr 1.020.926-1.12 0.871 0.817-0.929 PK 2 × 50/150/150 Bilayer 1 × 100/300/300Monolithic Parameter GMR 90% CI GMR 90% CI Lamivudine AUC0-∞ 1.020.975-1.07 1.09 1.05-1.12 Cmax 0.926  0.859-0.999 1.08 1.02-1.15 TDFAUC0-∞ 0.994 0.946-1.04 0.975 0.923-1.03  Cmax 0.912 0.808-1.03 0.8680.786-0.959 References: individual tablets of doravirine (100 mg),lamivudine (300 mg), TDF (300 mg) ^(a)Bilayer Formulation: 2 tablets of50 mg doravirine/150 mg lamivudine/150 mg TDF ^(b)MonolithicFormulation: 1 tablet of 100 mg doravirine/300 mg lamivudine/300 mg TDF^(c)Geometric Mean Ratio

The relative bioavailability of doravirine after administration ofeither the bilayer or monolithic formulation was comparable to thereference. The geometric mean ratios (GMR) of AUC_(0-∞), C_(max) andC_(24 hr) of doravirine were 1.00, 0.977, and 1.02, respectively, forthe bilayer tablet, indicating that bioavailability was the same as thereference. Slight decreases of 14%, 29%, and 13% were noted inAUC_(0-∞), C_(max) and C_(24 hr) of doravirine, respectively, afteradministration of the monolithic tablet compared to the reference withGMRs of 0.858, 0.713, and 0.871, respectively. Doravirine was absorbedwith a median t_(max) of 3 hr for the bilayer tablet and 4 hr for themonolithic tablet, comparable to the t_(max) of the reference (3 hr).The elimination t_(1/2) of doravirine (˜17-19 hr) was similar after allthree treatments.

The relative bioavailability of lamivudine was similar to the referencewith GMRs of AUC_(0-∞) and C_(max) of 1.02 and 0.926, respectively, forthe bilayer tablet, and the corresponding values for the monolithictablet were 1.09 and 1.08, respectively. Following administration as amonolithic or bilayer tablet, elimination t_(1/2) of lamivudine was notaltered compared to the reference (12.5 hr, and 12.6 hr respectively,compared to 11.6 hr). Lamivudine t_(max) was 2 hr for bilayer tablet and1 hr for the monolithic tablet, similar to the t_(max) of the reference(1 hr).

The relative bioavailability of tenofovir disoproxil fumarate whenadministered in both the bilayer and monolithic formulations wascomparable to the reference. The geometric mean ratios of AUC_(0-∞) andC_(max) of tenofovir disoproxil fumarate were 0.994 and 0.912,respectively, for the bilayer tablet, similar to the reference, whilethe values for the monolithic tablet were 0.975 and 0.868, respectively.A slight decrease (˜13%) of the geometric mean C_(max) was observed forthe monolithic tablet vs. the reference.

The median t_(max) for tenofovir disoproxil fumarate was 1 hr for boththe bilayer and monolithic tablets, and was similar to the t_(max) ofthe reference (1 hr). The elimination t_(1/2) of tenofovir disoproxilfumarate was similar after administration of the bilayer tablet (18.0hr), or monolithic tablet (17.8 hr) or as a co-administered tablet withlamivudine and tenofovir disoproxil fumarate tablets (18.1 hr).

Example 5 Biocomparabiliy of Bilayer Tablets (100 mg/300 mg/300 mg) andCo-Dosings

A biocomparability study was conducted to evaluate the comparativebioavailability of a bilayer fixed-dose combination (“FDC”) tabletcomprised of 100 mg doravirine, 300 mg lamivudine, and 300 mg tenofovirdisoproxil fumarate (TDF) to the bioavailability of co-administrationof:

-   -   Doravirine 100 mg oral tablet from Merck Sharp & Dohme Corp.,USA    -   Epivir® (lamivudine) 300 mg tablets from ViiV Healthcare UK        Limited, United Kingdom and    -   Viread® (tenofovir disoproxil fumarate) 245 mg tablets from        Gilead Sciences International Limited, United Kingdom

The FDC is a film-coated, bilayer tablet with doravirine in one layerand lamivudine and TDF in the other layer, as described herein.

1 × 100/300/300 Bilayer^(a) vs Co-Dosings^(b) Doravirine PK ParameterGMR^(c) 90% CI AUC_(0-∞) 1.01 0.94-1.08 AUC_(0-last) 1.02 0.95-1.09C_(max) 0.99 0.91-1.09 C_(24 hr) 1.02 0.94-1.12 PK Parameter GMR 90% CILamivudine AUC0-∞ 1.04 1.00-1.09 AUC_(0-last) 1.04 1.00-1.08 C_(max)1.00 0.91-1.09 TDF AUC_(0-∞) 0.98 0.93-1.03 AUC_(0-last) 0.99 0.94-1.04C_(max) 0.87 0.78-0.97 ^(a)Bilayer Formulation: 1 tablet of 100 mgdoravirine/300 mg lamivudine/300 mg TDF ^(b)Reference: individualtablets of DORAVIRINE (100 mg), Epivir ® (300 mg), Viread ® (245 mg)^(c)Geometric Mean Ratio

As shown above, the pharmacokinetics of doravirine, lamivudine, andtenofovir disoproxil fumarate were generally similar when administeredas a bilayer fixed-dose combination or the individual components. Whiletenofovir disoproxil fumarate C_(max) was slightly decreased afteradministration of the bilayer fixed-dose combination tablet, compared toadministration as Viread®, this decrease is not expected to beclinically meaningful.

Example 6 Chemical Stability Data for Bilayer Tablets (100 mg/300 mg/300mg)

The re-evaluation date (“RED”) for the FDC (100 mg doravirine/300 mgtenofovir disoproxil fumarate/300 mg lamuvidine) film-coated bilayertablet is 24 months (worldwide) stored at 2 to 25° C., based on 12-monthprobe stability data generated at 30° C./65% RH. The tablets werepackaged in 120-mL high-density polyethylene (“HDPE”) bottles withinduction-sealed caps and 4 g or more of desiccant. Alternativepackaging configurations, such as 90 mL or 100 mL HDPE bottles with atleast 3 g or 4 g of desiccant, respectively, could be used. Thealternative packaging configurations should provide similar, if notbetter humidity control compared to the primary package. The RED is thecurrently assigned shelf-life, based on the available data at the time,and can be extended with additional stability data from latertimepoints. Hence, the eventual or achievable commercial shelf life canbe and is expected to be longer than the mentioned RED. The tables belowprovide analysis of the assay and degradates for each of DORAVIRINE,lamivudine and TDF, after storage at various temperature/RH conditionsat various time points. The mono-POC degradate in TDF is the keydegradate which governs the shelf-life. The specification for mono-POCin the fixed-dose combination tablet is 3.5% wt.

Assay/Degradates for Film-Coated Bilaver Tablet (“FCT”) 100 mg/300mg/300 mg: Doravirine

Storage Timepoints Assay 1.28RRT Condition (months) (% claim) (% claim) 5° C./amb RH closed 1 97.99 0.03 25° C./60% RH closed 1 96.39 0.04 30°C./65% RH closed 1 95.20 0.05 40° C./75% RH closed 1 97.36 0.07 25°C./60% RH closed 2 98.22 0.05 30° C./65% RH closed 2 98.82 0.06 40°C./75% RH closed 2 97.92 0.09 25° C./60% RH closed 5 96.73 0.07 30°C./65% RH closed 5 96.98 0.09 40° C./75% RH closed 5 97.79 0.10 25°C./60% RH closed 8 96.34 0.07 30° C./65% RH closed 8 96.33 0.09 30°C./65% RH closed 12 98.32 0.10Assay/Degradates for Film-Coated Bilayer Tablet 100 mg/300 mg/300 mgFCT: Lamivudine

Storage Timepoints Assay 0.39RRT Condition (months) (% claim) (% claim) 5° C./amb RH closed 1 100.06 ND 25° C./60% RH closed 1 100.86 ND 30°C./65% RH closed 1 101.03 ND 40° C./75% RH closed 1 100.51 ND 25° C./60%RH closed 2 100.15 ND 30° C./65% RH closed 2 99.88 ND 40° C./75% RHclosed 2 100.49 ND 25° C./60% RH closed 5 99.67 ND 30° C./65% RH closed5 100.7 ND 40° C./75% RH closed 5 99.33 0.07 25° C./60% RH closed 8100.94 ND 30° C./65% RH closed 8 98.87 ND 30° C./65% RH closed 12 99.67NDAssay/Degradates for Film-Coated Bilaver Tablet 100 mg/300 mg/300 mgFCT: TDF

Storage Timespoints Assay Degradates (% claim) Condition (months) (%claim) 0.53RRT 0.59RRT 0.62RRT 0.66RRT 0.69RRT  5° C./amb RH 1 102.120.58 ND ND ND ND 25° C./60% R 1 100.88 0.62 0.01 ND ND ND 30° C./65% R 1101.40 0.66 0.02 ND ND ND 40° C./75% R 1 101.01 0.85 0.09 ND ND ND 25°C./60% R 2 103.28 0.68 0.01 ND ND ND 30° C./65% R 2 102.13 0.75 0.03 NDND ND 40° C./75% R 2 101.69 1.06 0.13 0.04 ND ND 25° C./60% R 5 100.290.77 0.04 ND ND ND 30° C./65% R 5 101.13 0.92 0.07 ND ND ND 40° C./75% R5 100.54 1.53 0.22 0.15 0.09 0.08 25° C./60% R 8 101.78 0.84 0.05 0.04ND ND 30° C./65% R 8 98.83 1.01 0.09 0.05 0.04 0.04 30° C./65% R 12100.49 1.20 0.10 0.05 0.05 0.06 (*) mono-POC is expressed as % LC byweight relative to TDF ND: Not detected RH: Relative Humidity RRT:Relative Retention Time (compared to the parent drug in a column)

Example 7 100 mg Doravirine/300 mg Lamivudine/300 mg TenofovirDisoproxil Fumarate Bilayer Tablets

Amount Percentage in Components Function [mg] Each Layer Layer 1 Intra-granular Doravirine¹ Active 100.0 12.8% Hypromellose acetate succinate -Polymer 400.0 51.3% LG (HPMC-ASLG)¹ Acetone² Solvent — Water, Purified²Solvent — Microcrystalline Cellulose Diluent 224.0 28.7% CroscarmelloseSodium Disintegrant 24.0  3.1% Colloidal Silica Glidant 4.00 0.51%Magnesium Stearate Lubricant 2.00 0.26% Extra- granular CroscarmelloseSodium Disintegrant 24.00  3.1% Magnesium Stearate Lubricant 2.00 0.26%Layer 1 Weight 780  100% Layer 2 Intra- granular Tenofovir DisoproxilFumarate Active 300.0 38.5% Microcrystalline Cellulose Diluent 51.93 6.7% Croscarmellose Sodium Disintegrant 11.70  1.5% Colloidal SilicaGlidant 3.12 0.40% Sodium Stearyl Fumarate Lubricant 4.50 0.58%Magnesium Stearate Lubricant 4.50 0.58% Lamivudine Active 300.0 38.5%Microcrystalline Cellulose Diluent 55.68  7.1% Croscarmellose SodiumDisintegrant 11.70  1.5% Colloidal Silica Glidant 3.12 0.40% SodiumStearyl Fumarate Lubricant 2.25 0.29% Magnesium Stearate Lubricant 2.250.29% Extra- granular Croscarmellose Sodium Disintegrant 23.40  3.0%Magnesium Stearate Lubricant 6.00 0.77% Layer 2 Weight 780  100% CoreTablet Weight 1560 Opadry II 39K Film Coat Film Coat 39.00 Water,Purified² Solvent — Film-Coated Tablet Weight 1599 ¹Prepared as spraydried intermediate ²Removed during processing

Doravirine Layer Granulation.

Doravirine spray dried intermediate, microcrystalline cellulose,colloidal silica (sieved thru 34 T Mesh with microcrystalline cellulose)and croscarmellose sodium were blended in 40 L Bohle bin at 25 rpm for10 min. Magnesium stearate was sieved through 74 T Mesh and added to theblender, which was blended at 25 rpm for 5 min. The lubricated blend wasroller-compacted using the Alexanderwerk WP-120 at the followingsettings: 40 mm knurled roll, 33 bars, 2.0 mm gap, 2.0 mm/1.0 mm wiremesh screens. Then, croscarmellose sodium was added to Bohle bin andblended at 25 rpm for 10 min. Finally, magnesium stearate was sievedthrough 74 T Mesh and added to the blender, which was blended at 25 rpmfor additional 5 min.

LAM/TDF Layer Blend.

(i) LAM Blending and Roller Compaction. Lamivudine (sieved thru 22 TMesh), microcrystalline cellulose, colloidal silica (sieved thru 34 TMesh with microcrystalline cellulose) and croscarmellose sodium wereblended in 40 L Bohle bin at 25 rpm for 10 min. Sodium stearyl fumarateand magnesium stearate was sieved through 74 T Mesh and added to theblender, which was blended at 25 rpm for 5 min. The lubricated blend wasroller-compacted using the Alexanderwerk WP-120 at the followingsettings: 40 mm knurled roll, 36 bars, 2.0 mm gap, 2.0 mm/1.0 mm wirescreens. (ii) TDF blending and roller compaction. TDF, microcrystallinecellulose, colloidal silica (sieved thru 34 T mesh with microcrystallinecellulose), croscarmellose sodium were blended in 40 L Bohle bin at 25rpm for 10 min. Sodium stearyl fumarate and magnesium stearate wassieved through 74 T Mesh and added to the blender, which was blended at25 rpm for 5 min. The lubricated blend was roller-compacted using theAlexanderwerk WP-120 at the following settings: 40 mm knurled roll, 22bars, 2.0 mm gap, 2.0 mm/1.0 mm wire screens. (iii) LAM and TDFgranulations blending and lubrication. LAM granulation, TDF granulationand croscarmellose sodium were added to a Bohle bin and blended at 25rpm for 10 min. Finally, magnesium stearate was sieved through 60 Meshand added to the blender, which was blended at 25 rpm for 5 min.

Bilayer Compression.

Doravirine lubricated granules (layer 1) and LAM/TDF lubricated granules(layer 2) were compressed into bilayer tablets on the Fette 3090 press(14 stations) using the following parameters (oval tooling,0.850″×0.445″, 780 mg layer 1 fill weight, 780 mg layer 2 fill weight,24 kp hardness, 5 kN tamping force, 35 kN main compression force, 10 rpmturret speed).

Film Coating.

An aqueous suspension of Opadry 39K, yellow, 18% by weight, wasprepared. The compressed tablets were film-coated in the Vector LCDS 2.5L, using the following parameters (1.5 kg tablet load, exhaust temp=40°C., air flow=40 cfm, pan speed=12 rpm, spray rate=7.0 g/min).

Example 8 100 mg Doravirine/300 mg Lamivudine/300 mg TenofovirDisoproxil Fumarate Bilayer Tablets

Amount Percentage in Components Function [mg] Each Layer Layer 1 Intra-granular Doravirine¹ Active 100.0 12.8% Hypromellose acetate succinate -Polymer 400.0 51.3% LG (HPMC-ASLG)¹ Acetone² Solvent — Water, Purified²Solvent — Microcrystalline Cellulose Diluent 224.0 28.7% CroscarmelloseSodium Disintegrant 24.0  3.1% Colloidal Silica Glidant 4.00 0.51%Magnesium Stearate Lubricant 2.00 0.26% Extra- granular CroscarmelloseSodium Disintegrant 24.00  3.1% Magnesium Stearate Lubricant 2.00 0.26%Layer 1 Weight 780  100% Layer 2 Intra- granular Tenofovir DisoproxilFumarate Active 300.0 43.80 Croscarmellose Sodium Disintegrant 13.191.93% Hydroxypropylcellulose - EXF Binder 16.49 2.41% Lamivudine Active300.0 43.80%  Croscarmellose Sodium Disintegrant 13.19 1.93%Hydroxypropylcellulose - EXF Binder 16.49 2.41% Extra- granularCroscarmellose Sodium Disintegrant 20.80  3.0% Magnesium StearateLubricant 4.80 0.70% Layer 2 Weight 685  100% Core Tablet Weight 1465Opadry II 39K Film Coat Film Coat 36.6 Water, Purified² Solvent —Film-Coated Tablet Weight 1501.6 ¹Prepared as spray dried intermediate²Removed during processing

Doravirine Layer Granulation.

Doravirine spray dried intermediate, microcrystalline cellulose,colloidal silica (sieved thru 30 Mesh with microcrystalline cellulose),croscarmellose sodium were blended in 40 L Bohle bin at 25 rpm for 10min. Magnesium stearate was sieved through 60 Mesh and added to theblender, which was blended at 25 rpm for 5 min. The lubricated blend wasroller-compacted using the Alexanderwerk WP-120 at the followingsettings: 40 mm knurled roll, 34 bars, 2.0 mm gap, 2.0 mm/1.0 mm wiremesh screens. Then, croscarmellose sodium was added to the Bohle bin andblended at 25 rpm for 10 min. Finally, magnesium stearate was sievedthrough 60 Mesh and added to the blender, which was blended at 25 rpmfor additional 5 min.

LAM/TDF Layer Blend.

(i) LAM wet granulation. Lamivudine, croscarmellose sodium andhydropropyl cellulose were charged into a 10 L FIELDER blender (1.8 kgtotal) and blended for 1 min at impeller speed of 300 rpm. Then, theblend was wet-granulated with water as a granulation solution at thefollowing settings: 300 rpm impeller speed, 1800 rpm chopper speed, 66g/min solution delivery for 10 min. The wet granules were tray-dried at35° C. The dried granules were milled using a Co-Mil with 40G screen at1500 rpm. (ii) TDF wet granulation. TDF, croscarmellose sodium andhydropropyl cellulose were charged into 10 L Fielder (2 kg total) andblended for 1 min at impeller speed of 300 rpm. Then, the blend waswet-granulated with water as a granulation solution at the followingsettings: 300 rpm impeller speed, 1800 rpm chopper speed, 100 g/minsolution delivery for 10 min. The wet granules were tray-dried at 35° C.The dried granules were milled using a Co-Mil with 40G screen at 1500rpm. (iii) LAM and TDF granulations blending and lubrication. LAMgranulation, TDF granulation, and croscarmellose sodium were added to aBohle bin and blended at 25 rpm for 10 min. Finally, magnesium stearatewas sieved through 60 Mesh and added to the blender, which was blendedat 25 rpm for 5 min.

Bilayer Compression.

Doravirine lubricated granules (layer 1) and LAM/TDF lubricated granules(layer 2) were compressed into bilayer tablets on the Fette 3090 press(7 stations) using the following parameters (oval tooling,0.850″×0.445″, 780 mg layer 1 fill weight, 685 mg layer 2 fill weight,26 kp hardness, 5 kN tamping force, 25 kN main compression force, 10 rpmturret speed).

Film Coating.

An aqueous suspension of Opadry 39K, yellow, 18% by weight, wasprepared. The compressed tablets were film-coated in the Vector LCDS 2.5L, using the following parameters (1.5 kg tablet load, exhaust temp=40°C., air flow=40 cfm, pan speed=12 rpm, spray rate=6.5 g/min).

Example 9 Chemical Stability Data for Bilayer Tablets (100 mg/300 mg/300mg)

0.53RRT mono-POC (% area) mono-POC Growth Formulation Example 5° C. 60°C. (% area) over 3 weeks EXAMPLE 2 0.71 3.47 2.76 EXAMPLE 7 0.69 2.311.62 EXAMPLE 8 0.65 1.67 1.02

The stability of different configurations of bilayer tablets in relationto tenofovir mono-POC formation is shown above. The differentconfigurations are described in Examples 2, 7 and 8 wherein thedoravirine layer is similar but the TDF/lamivudine consisting secondlayer is either co-granulated or separately granulated via dry or wetgranulation techniques. The stability when TDF and lamivudine arespatially separated is improved relative to that when TDF and lamivudineare co-granulated.

What is claimed is:
 1. A pharmaceutical composition, which is a bilayertablet, comprising an amorphous dispersion formulation of doravirine inthe first layer, and lamivudine and tenofovir disoproxil fumarate in thesecond layer.
 2. The pharmaceutical composition of claim 1 wherein theamorphous dispersion formulation of doravirine comprises doravirine anda polymer.
 3. The pharmaceutical composition of claim 2 wherein thepolymer is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, hydroxpropyl methyl cellulose phthalate,cellulose acetate phthalate, cellulose acetate trimellitate, methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate,cellulose acetate terephthalate, cellulose acetate isophthalate,polyvinylpyrrolidinone and polyvinylpyrrolidinone-polyvinylacetatecopolymers.
 4. The pharmaceutical composition of claim 3 wherein thepolymer is hydroxypropyl methyl cellulose acetate succinate.
 5. Thepharmaceutical composition of claim 1 wherein the first layer comprisesan amorphous dispersion formulation of doravirine, a glidant, diluents,disintegrants, and lubricants.
 6. The pharmaceutical composition ofclaim 5 wherein the first layer comprises a glidant that is selectedfrom the group consisting of colloidal silica, silicone dioxide, talcand starch; diluents that are selected from the group consisting oflactose, lactose anhydrous, lactose monohydrate, mannitol,microcrystalline cellulose, calcium phosphate dibasic, calcium carbonateand magnesium carbonate; disintegrants that are selected from the groupconsisting of croscarmellose sodium, starch, crospovidone, and sodiumstarch glycolate; and lubricants that are selected from the groupconsisting of magnesium stearate, stearic acid or sodium stearylfumarate.
 7. The pharmaceutical composition of claim 6 wherein the firstlayer comprises a glidant that is colloidal silica; a diluent that ismicrocrystalline cellulose; a disintegrant that is croscarmellosesodium; and a lubricant that is magnesium stearate.
 8. Thepharmaceutical composition of claim 1 wherein the second layer compriseslamivudine, tenofovir disoproxil fumarate, a glidant, diluents,disintegrants, and lubricants.
 9. The pharmaceutical composition ofclaim 8 wherein the second layer comprises a glidant that is selectedfrom the group consisting of colloidal silica, silicone dioxide, talcand starch; diluents that are selected from the group consisting oflactose, lactose anhydrous, lactose monohydrate, mannitol,microcrystalline cellulose, calcium phosphate dibasic, calcium carbonateand magnesium carbonate; disintegrants that are selected from the groupconsisting of croscarmellose sodium, starch, crospovidone, and sodiumstarch glycolate; lubricants that are selected from the group consistingof magnesium stearate, stearic acid and sodium stearyl fumerate.
 10. Thepharmaceutical composition of claim 9 wherein the second layer comprisesa glidant that is colloidal silica; a diluent that is microcrystallinecellulose; a disintegrant that is croscarmellose sodium; and lubricantsthat are magnesium stearate and sodium stearyl fumarate.
 11. Thepharmaceutical composition of claim 1 wherein lamivudine and tenofovirdisoproxil fumarate are co-granulated.
 12. The pharmaceuticalcomposition of claim 1 wherein lamivudine and tenofovir disoproxilfumarate are separately granulated.
 13. The pharmaceutical compositionof claim 1 comprising a film coat.
 14. The pharmaceutical composition ofclaim 1 comprising a polishing aid.
 15. The pharmaceutical compositionof claim 1 comprising 50 mg of doravirine, 150 mg of lamivudine and 150mg of tenofovir disoproxil fumarate.
 16. The pharmaceutical compositionof claim 1 comprising 100 mg of doravirine, 300 mg of lamivudine and 300mg of tenofovir disoproxil fumarate.
 17. The pharmaceutical compositionof claim 1 comprising: Amount Components [mg] Layer 1 IntragranularDoravirine 50.00 Hypromellose acetate succinate - 200.0 LG (HPMC-ASLG)Microcrystalline Cellulose 107.5 Lactose Monohydrate 107.5Croscarmellose Sodium 15.00 Colloidal Silica 2.50 Magnesium Stearate1.25 Extragranular Croscarmellose Sodium 15.00 Magnesium Stearate 1.25Layer 1 Weight 500.0 Layer 2 Intragranular Lamivudine 150.0 TenofovirDisoproxil Fumarate 150.0 Microcrystalline Cellulose 120.0 LactoseMonohydrate 55.0 Croscarmellose Sodium 10.00 Magnesium Stearate 1.25Extragranular Croscarmellose Sodium 10.00 Magnesium Stearate 3.75 Layer2 Weight 500.0 Core Tablet Weight 1000.0 Opadry II 39K Film Coat 25.00Film-Coated Tablet Weight 1025.0


18. The pharmaceutical composition of claim 1 comprising: AmountComponents [mg] Layer 1 Intragranular Doravirine 100.0 Hypromelloseacetate succinate - 400.0 LG (HPMC-ASLG) Microcrystalline Cellulose224.0 Croscarmellose Sodium 24.0 Colloidal Silica 4.00 MagnesiumStearate 2.00 Extragranular Croscarmellose Sodium 24.00 MagnesiumStearate 2.00 Layer 1 Weight 780.0 Layer 2 Intragranular Lamivudine300.0 Tenofovir Disoproxil Fumarate 300.0 Microcrystalline Cellulose103.8 Croscarmellose Sodium 23.4 Colloidal Silica 7.80 MagnesiumStearate 7.80 Sodium Stearyl Fumarate 7.80 Extragranular CroscarmelloseSodium 23.40 Magnesium Stearate 6.00 Layer 2 Weight 780.0 Core TabletWeight 1560 Opadry II 39K Film Coat 39.00 Carnauba Wax 0.05 Film-CoatedTablet Weight 1599


19. The pharmaceutical composition of claim 1 comprising: AmountComponents [mg] Layer 1 Intragranular Doravirine 100.0 Hypromelloseacetate succinate - 400.0 LG (HPMC-ASLG) Microcrystalline Cellulose224.0 Croscarmellose Sodium 24.0 Colloidal Silica 4.00 MagnesiumStearate 2.00 Extragranular Croscarmellose Sodium 24.00 MagnesiumStearate 2.00 Layer 1 Weight 780 Layer 2 Intragranular TenofovirDisoproxil Fumarate 300.0 Microcrystalline Cellulose 51.93Croscarmellose Sodium 11.70 Colloidal Silica 3.12 Sodium StearylFumarate 4.50 Magnesium Stearate 4.50 Intragranular Lamivudine 300.0Microcrystalline Cellulose 55.68 Croscarmellose Sodium 11.70 ColloidalSilica 3.12 Sodium Stearyl Fumarate 2.25 Magnesium Stearate 2.25Extragranular Croscarmellose Sodium 23.40 Magnesium Stearate 6.00 Layer2 Weight 780 Core Tablet Weight 1560 Opadry II 39K Film Coat 39.00Film-Coated Tablet Weight 1599